New tetracyclic 1,4-oxazepines constructed via practically simple tandem condensation strategy from readily available synthons

Article abstract of DOI:10.1016/j.tet.2013.12.026

A streamlined synthetic methodology towards novel tetracyclic 1,4-oxazepines from readily available precursors is described. The compounds, designed as more soluble version of the earlier described, poorly soluble dibenzo[b,f][1,4]oxazepines, were obtained in high yields and as a single regioisomer as a result of three tandem chemical events - nucleophilic aromatic substitution, Smiles rearrangement and denitrocyclization.

Full text of DOI:10.1016/j.tet.2013.12.026

Accepted Manuscript
New tetracyclic 1,4-oxazepines constructed via practically simple tandem
condensation strategy from readily available synthons
Alexander V. Sapegin, Stanislav A. Kalinin, Alexey V. Smirnov, Mikhail V. Dorogov,
Mikhail Krasavin
PII:
S0040-4020(13)01880-2
10.1016/j.tet.2013.12.026
TET 25110
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 14 October 2013
Revised Date: 28 November 2013
Accepted Date: 10 December 2013
Please cite this article as: Sapegin AV, Kalinin SA, Smirnov AV, Dorogov MV, Krasavin M, New
tetracyclic 1,4-oxazepines constructed via practically simple tandem condensation strategy from readily
available synthons, Tetrahedron (2014), doi: 10.1016/j.tet.2013.12.026.
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ACCEPTED MANUSCRIPT
New tetracyclic 1,4-oxazepines constructed via practically simple tandem
condensation strategy from readily available synthons
Alexander V. Sapegin, Stanislav A. Kalinin, Alexey V. Smirnov, Mikhail V. Dorogov and
*
Mikhail Krasavin
1

ACCEPTED MANUSCRIPT
New tetracyclic 1,4-oxazepines constructed via practically simple tandem
condensation strategy from readily available synthons
a
a
a
a
Alexander V. Sapegin, Stanislav A. Kalinin, Alexey V. Smirnov, Mikhail V. Dorogov and
*
b
Mikhail Krasavin
a
The Ushinsky Yaroslavl State Pedagogical University, 108 Respublikanskaya St., Yaroslavl,
1
50000, Russian Federation
b
Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111,
Australia
Phone: +61(0)73735 6041.Fax: +61(0)73735 6001.
E-mail: mkrasavin@hotmail.com
Abstract: a streamlined synthetic methodology toward novel tetracyclic 1,4-oxazepines from
readily available precursors is described. The compounds, designed as more soluble version
of the earlier described, poorly soluble dibenzo[b,f][1,4]oxazepines, were obtained in high
yields and as a single regioisomer as a result of three tandem chemical events – nucleophilic
aromatic substitution, Smiles rearrangement, and denitrocyclization.
Keywords: bioisosteres, solubilizing groups, oxazepines, tetracyclic, privileged structures,
nucleophilic aromatic substitution, Smiles rearrangement, denitrocyclization.
1
. Introduction
Considering the synthetic and commercial availability of 2-chloronitrobenzenes (as well as
their heterocyclic analogs), new ring-forming processes that utilize these synthons in
combination with various bis-nucleophiles and involve aromatic nucleophilic substitution
1
2
followed by denitrocyclization should be sought after. Previously, we described an efficient
access to a tricyclic dibenzo[b,f][1,4]oxazepinecore using secondary salicylamides in
3
combination with 2-chloronitrobenzenes (this work was later repeated by others in expanded
format). More recently, we replaced the bis-nucleophilic salicylamides with the readily
available 2-(1H-pyrazol-5-yl)phenols 1 and gained a facile access to the rare tetracyclic
dibenzo[b,f]pyrazolo[1,5-d][1,4]oxazepines 2 in a one-step process that was shown to involve
2

ACCEPTED MANUSCRIPT
4
Smiles rearrangement. When ‘decorated’ with different types of appendages, the
dibenzo[b,f][1,4]oxazepine scaffold results in compounds with vastly different biological
5
activities, as evident from a literature review and therefore this heterocycle should be
6
regarded as privileged. The biological profiling of 2 in our laboratories, however, has been
severely hampered by a markedly low solubility (in organic solvents as well as in aqueous
medium), which is unsurprising for a tetracyclic structure containing two benzene rings
7
(
these features usually result in a tight crystal packing and low solubility). We therefore
became interested in developing a synthesis of the aza-analogs of these compounds, namely,
benzo[f]pyrazolo[1,5-d]pyrido[3,2-b][1,4]oxazepines 3. The addition of a nitrogen atom was
expected to significantly ‘de-symmetrize’ the scaffold, compared to its dibenzo counterpart,
8
which is a known approach to increasing the solubility by weakening the crystal packing. In
particular, the pyrido compounds 3 were expected to be protonated at near-neutral pH and
9
thus be more soluble in the biological assay medium.
So, we set out to investigate the condensation of 2-(1H-pyrazol-5-yl)phenols1with various 2-
chloro-3-nitropyridines
4
via nucleophilic aromatic substitution followed by
denitrocyclization, in order to establish its scope as well as regiochemical outcome (Scheme
4
1
). As we showed previously, the latter allows us to conclude whether the ring-forming
process in question is accompanied by Smiles rearrangement.
4
Scheme 1. Dibenzo[b,f][1,4]oxazepines 2 (synthesized as described earlier ) and their aza-
analogs 3 studied in this work.
3

ACCEPTED MANUSCRIPT
2
. Results and discussion
To study the applicability and scope of the envisioned condensation, 2-chloro-3-
nitropyridines 4a-e in combination with 2-(1H-pyrazol-5-yl)phenols 1a-f were selected
(Figure 1).
Figure 1. Condensation partners selected for the present study.
Although all compounds 4a-f are advertised as available commercially (according to
®
SciFinder ), we were only able to source 4a and 4c in the multi-gram quantities required for
methodology development. Compounds 4b and 4d-e were prepared from the respective 2-
hydroxy-3-nitropyridines 5. Compound 5a was synthesized via nitration of the readily
available 2-hydroxypyridine 6 while 5b-c were accessed via nitration of 2-aminopyridines 7
followed by diazotization. All these transformations (Scheme 2) were distinctly high-
yielding.
Scheme 2. Synthesis of 2-chloro-3-nitropyridines 4b and 4d-e.
CN
HO
N
6
0
-5 o
then 70 oC, 5h
C
HNO3
R3
R3
R3
O N
R3
O N
O N
POCl3
2
HNO , H SO
2
NaNO , H SO
4
2
3
2
4
2
2
0 o
overnight
C
r. t.
5 o
C
r. t.
DMF
reflux, 12h
H N
N
H N
N
HO
N
Cl
N
2
2
7
a, R3 = Br (71%)
5a, R3 = CN (67%)
5b, R = Br (89%)
3
8
8
4b, R = CN (73%)
4d, R = Br (81%)
4e, R = CF
3
3
3
b, R = CF
3
(77%)
3
3
5c, R = CF
3
(73%)
3
(72%)
2
-(1H-Pyrazol-5-yl)phenols 1a-d were prepared, on a multi-gram scale, as we described
4
previously. Trifluoromethyl- (1e) and methoxycarbonyl-substuted (1f) compounds were
4

ACCEPTED MANUSCRIPT
prepared by ring-opening of the respective 4H-chromen-4-ones 9a-b. The latter were
prepared via Knoevenagel condensation of 2-hydroxyacetophenone with trifluoroacetic
1
0
11
anhydride and dimethyl oxalate, respectively (Scheme 3).
Scheme 3. Preparation of 2-(1H-pyrazol-5-yl)phenols 1a-f.
R2
O
R1
OH
R2
Na
O
OEt
R1
1
a-d:
+
neat,
reflux 2 h
OH
O
.
N H H O,
2 4 2
ONa
AcOH
EtOH, reflux
R2
N
TFAA
5
h
O
O
O
py, 80 o
.
R1
C
N H H O
2 4 2
N

R1
R2
3
h
H
1
e-f:
EtOH
reflux
5 h
R2
OH
1a:
H

1b:
H

H
Et
OH
(MeOCO)2
1
a-f
2
9
9
a, R = CF3
b, R2 = COOMe
1c:
Me Me
1d:
Cl
Me
e:
H
CF3
NaOMe
MeOH, reflux, 3 h
1
1
f:
H
COOMe
With the diverse set of synthons 1a-f and 4a-e available to us, we set off to investigate their
base-promoted condensation to yield the targetbenzo[f]pyrazolo[1,5-d]pyrido[3,2-
b][1,4]oxazepines 3 (via direct nucleophilic aromatic substitution followed by
denitrocyclization) as well as to determine its regiochemical outcome. To our delight, the
simple conditions that we had identified earlier (involving heating the reaction partners with
4
anhydrous K
2
CO
3
in DMF) proved quite suitable in this case as well (Scheme 4). Reactions
were complete in 8-36 hours providing good to excellent yields of the condensation products
(Table 1). Although we have not performed exact measurements of these products (3), their
3
greater solubility (compared to dibenzo[b,f][1,4]oxazepines 2) was apparent. More
specifically, if pouring the DMF solutions containing 2 into water had earlier led to
4
immediate precipitation of the latter, but a similar workup turned out to be not applicable for
the isolation of 3. The aza-compounds 3 failed to precipitate and had to be recovered by
DCM extraction (concentration of the DMF solutions prior to pouring them in water finally
brought about the desired precipitation – see Experimental Section).
Scheme 4. Synthesis of benzo[f]pyrazolo[1,5-d]pyrido[3,2-b][1,4]oxazepines 3.
5

ACCEPTED MANUSCRIPT
a
Table 1.Benzo[f]pyrazolo[1,5-d]pyrido[3,2-b][1,4]oxazepines3 synthesized in this work.
1
2
3
Compound
R
R
R
Reaction
time (h)
8
T, °C
Isolated
yield (%)
62
3
a
H
H
H
H
CF
3
80
80
3
b
COOMe
10
6
79
71
84
68
83
54
77
82
62
86
84
50
53
60
75
59
81
3
c
H
H
NO
Br
2
40
3
d
H
Et
12
8
110
80
3
e
H
Et
CF
3
3
f
H
Et
CN
H
8
80
3
g
Me
Me
Me
Cl
Cl
Cl
H
Me
Me
Me
Me
Me
Me
36
10
6
110
80
3
h
COOMe
3
i
NO
H
2
40
3
j
36
10
6
110
80
3
k
COOMe
3
l
NO
H
2
40
3
m
CF
CF
CF
3
36
12
8
110
110
80
3
n
H
3
3
Br
3
o
p
q
H
CN
Br
3
H
COOMe
COOMe
COOMe
12
8
110
80
3
H
CF
3
3
r
H
CN
8
80
Knowing the regiochemistry of the products 3 was important for determining whether or not
the condensation of 1 and 4 leading to them was accompanied by the Smiles rearrangement
2
,4
(
as was earlier established for similar reactions ). Under the reaction conditions, pyrazole
nitrogen alone is notcapable of reaction with any of the 2-chloro-3-nitropyridine partners 4a-f
as was established by the none-conversions observed in the reactions of 4a-e with 3-methyl-
5
-phenyl-1H-pyrazole (Scheme 5). Therefore, formation of regioisomer B would attest to the
6

ACCEPTED MANUSCRIPT
absence of the Smiles rearrangement en route to 3 while regioisomer A could only form if the
rearrangement took place (Scheme 6).
Scheme 5. Failed reactions of 3-methyl-5-phenyl-1H-pyrazole with 2-chloro-3-nitropyridines
4
a-f.
Scheme 6. Possible mechanistic pathways leading to regiosomers A and B of compounds 3.
The correlational NMR techniques (NOESY, HMBC, HSQC) were not particularly helpful in
establishing the regiochemistry of products 3a-r. Fortunately, we were able to obtain a
12
single-crystal X-ray structure of a representative benzo[f]pyrazolo[1,5-d]pyrido[3,2-
b][1,4]oxazepine (3l) that clearly demonstrated that compounds 3 belonged to regioisomeric
series A (Figure 2).
Figure 2.Single-crystal X-ray structure of compound 3l.
7

ACCEPTED MANUSCRIPT
3
.
Conclusion
In summary, we have developed a streamlined synthetic methodology toward novel
tetracyclic 1,4-oxazepines from readily available precursors. The compounds were obtained
in high yields and as a single regioisomer as a result of three tandem chemical events –
nucleophilic aromatic substitution, Smiles rearrangement, denitrocyclization. The compounds
obtained were remarkably more soluble in DMF-water mixtures compared to the
4
isostericdibenzo[b,f][1,4]oxazepines studied by us previously. The compounds prepared in
this work will be subject to physicochemical as well as biological profiling on which we will
report in due course.
4
. Experimental Section.
4
.1 General
All reactions were run in oven-dried glassware in atmosphere of nitrogen. Melting points
were measured with a BuchiВ-520 melting point apparatus and were not corrected.
Analytical thin-layer chromatography was carried out on Silufol UV-254silica gel plates
using an appropriate mixtures of ethyl acetate and hexane. Compounds were visualized with
1
13
short-wavelength UV light. H NMR and C NMR spectra were recorded on Bruker MSL-
00 spectrometers in DMSO-d using TMS as an internal standard. Elemental analyses were
3
6
obtained at Research Institute for Chemical Crop Protection (Moscow, Russia) using Carlo
ErbaStrumentazione 1106 analyzer. IR spectra were recorded on Perkin Elmer Spectrum RX1
FTIR spectrometer. All and reagents were obtained from commercial sources and used
14
without purification. DMF was dried according to the standard procedure and potassium
o
carbonate was dried at 200 C for 5 hours prior to use.
1
5
4
.1.1 6-Hydroxy-5-nitronicotinonitrile (5a). 6-Hydroxynicotinonitrile (2.40 g, 0.020 mol)
was added to cold concentrated HNO in small portions so as to maintain the temperature
within 0-5 °C range. The reaction mixture was stirred at that temperature for 2 h, heated at 70
C for 5 h, cooled to r. t. and then poured over ice. The precipitate formed was filtered off,
3
°
washed with water and dried at 60 °C overnight to provide the title compound (2.21 g, 67%)
1
as yellow solid. M.p. 290-292 °С. H NMR (DMSO-d
6
, 300 K, ppm) δ 12.83-13.39 (br s, 1H,
13
OH), 8.59 (d, 1H, J= 2.5 Hz, Py), 8.70 (d, 1H, J= 2.5 Hz, Py). C NMR (DMSO-d
6
, 300 K,
ppm) δ 164.1, 153.4, 142.7, 134.9, 120.7, 117.0. Anal. Calcd for C H N O : C, 43.65; H,
6
3
3
3
1
.83; N 25.45. Found: C, 43.52; H, 1.81; N, 25.58.
8

ACCEPTED MANUSCRIPT
4
.1.2 2-(Trifluoromethyl)-4H-chromen-4-one (9a). This compounds was prepared from 2-
10
hydroxyacetophenone as described earlier. The spectral data of the compound obtained
13 1
were consistent with the ones published: H NMR (DMSO-d
6
, 300 K, ppm) δ 8.08 (d, J =
7
.9 Hz, 1H, HAr), 7.92 (t, J = 7.5 Hz, 1H, HAr), 7.78 (d, J = 8.2 Hz, 1H, HAr), 7.59 (t, J = 7.9
13
Hz, 1H, HAr), 7.04 (s, 1H, HChromen). C NMR (DMSO-d
6
, 300 K, ppm) δ 176.8, 155.7, 152.3
(q, J = 39.0 Hz), 134.9, 126.3, 126.0, 124.1, 118.6 (q, J = 272.0 Hz); 118.4, 110.5.
4
.1.3 Methyl 4-oxo-4H-chromene-2-carboxylate (9b). This compounds was prepared from 2-
11
hydroxyacetophenone as described earlier. The spectral data of the compound obtained
14 1
were consistent with the ones published: H NMR (DMSO-d
6
, 300 K, ppm) δ 8.06 (d, J =
7
.9 Hz, 1H, H ), 7.88 (t, J = 8.9 Hz, 1H, H ), 7.74 (d, J = 8.5 Hz, 1H, H ), 7.54 (t, J = 7.5
Ar
Ar
Ar
13
Hz, 1H, HAr), 6.94 (s, 1H, HChromen), 3.94 (s, 3H, HCOOMe). C NMR (DMSO-d
δ 176.4, 163.2, 161.5, 157.8, 136.0, 127.5, 124.0, 122.1, 118.5, 116.2, 52.3.
6
, 300 K, ppm)
4
.2 General procedure for nitration of 2-aminopyridines 7.
-Aminopyridine 7 (0.020 mol) was added to ice-cold concentrated sulphuric acid and the
2
resulting solution was treated with concentrated nitric acid (1.09 mL, 0.024 mol) which was
added slowly so as to maintain the reaction temperature in 0-5 °C range. The resulting
solution was stirred at 0-5 °C for 1h, warmed up to r. t. and stirred at that temperature
overnight. It was then poured over ice and the pH was adjusted to 7-8 with 10% aq. NaOH
solution. The resulting precipitate was collected by filtration, washed with water and dried at
6
0 °C overnight to provide analytically pure 2-amino-3-nitropyridines.
1
6
4
2
2
.2.1 5-Bromo-3-nitro-pyridin-2-ylamine (8a). Yield – 3,081 mg (71%). Yellow solid, m.p.
1
07-209 °С. H NMR (DMSO-d
6
, 300 K, ppm) δ 8.27 - 8.39 (m, 2H, Py), 7.92 - 8.11 (br s,
, 300 K, ppm) δ 154.9, 152.7, 146.3, 130.1, 112.2. Anal.
3 2
O : C, 27.55; H, 1.85; N 19.27. Found: C, 27.46; H, 1.83; N, 19.37.
1
3
H, NH
2
). C NMR (DMSO-d
BrN
6
Calcd for C
5
H
4
1
7
4
.2.2 3-Nitro-5-trifluoromethyl-pyridin-2-ylamine (8b). Yield – 3,188 mg (77%). Yellow
1
6
solid, m.p. 192-194 °С. H NMR (DMSO-d , 300 K, ppm) δ 8.74 (s, 1H, Py), 8.57 (s, 1H,
13
Py).7.83-8.15 (br s, 2H, NH
27.2, 123.3, 118.0 (unresolved q). Anal. Calcd for C
Found: C, 34.69; H, 1.97; N, 13.58.
2
). C NMR (DMSO-d
6
, 300 K, ppm) δ 156.0, 151.8, 134.3,
1
6
H
4
F
3
N
3
O
2
: C, 34.80; H, 1.95; N 13.53.
9

ACCEPTED MANUSCRIPT
4
.3 General procedure for diazotization of 2-aminopyridines 8a-b.
2
-Amino-3-nitropyridine 8 (0.015 mol) was dissolved, on cooling with ice, in 70% sulfuric
2
acid and treated with a solution of NaNO (1.24 g) in water (8 mL) which was added
dropwise so as to maintain the reaction temperature in 0-5 °C range. The reaction was
allowed to warm up to r. t. and stirred at that temperature for 3 h. The precipitate formed was
isolated by filtration, washed with water and dried at 60 °C overnight.
18
4
.3.1 5-Bromo-3-nitropyridin-2-ol (5b). Yield – 2,924 mg (89%). Light yellow solid, m.p.
1
2
42-244 °С. H NMR (DMSO-d
6
, 300 K, ppm) δ 12.65-13.54 (br s. 1H, PyOH), 8.67 (d, 1H,
1
3
J= 2.4 Hz, Py), 8.54 (d, 1H, J= 2.4 Hz, Py). C NMR (DMSO-d
49.1, 145.3, 138.8, 117.1. Anal. Calcd for C BrN : C, 27.42; H, 1.38; N 12.79. Found:
C, 27.34; H, 1.39; N, 12.86.
6
, 300 K, ppm) δ 159.5,
1
5
H
3
2 3
O
19
4
.3.2 3-Nitro-5-trifluoromethylpyridin-2-ol (5c). Yield – 2,278 mg (73%). Yellow solid,
1
m.p. 176-178 °С. H NMR (DMSO-d
6
, 300 K, ppm) δ 12.70-13.05 (br s, 1H, OH), 8.77 (d,
1
3
1
1
1
H, J= 2.7 Hz, Py), 8.60 (d, 1H, J= 2.7 Hz, Py). C NMR (DMSO-d
6
, 300 K, ppm) δ 158.6,
44.2, 138.1, 129.9, 123.1, 114.7 (q). Anal. Calcd for C H F N O : C, 34.63; H, 1.45; N
6
3
3
2
3
3.46. Found: C, 34.57; H, 1.42; N, 13.50.
4
.4 General procedure for preparation of 2-chloro-3-nitropyridines 4.
2
-Hydroxy-3-nitropyridine 5 (0.015 mol) was suspended in POCl (15 mL). Anhydrous DMF
3
(
2 mL) was added and the resulting mixture was heated at reflux for 12 h. The excess of
POCl was removed by distillation, the residue was taken up in a mixture of DCM with ice
and the mixture was stirred for 30 min. The organic layer was separated, washed with water
3x), dried over anhydrous Na SO , filtered and concentrated to yield analytically pure
product.
3
(
2
4
2
0
4
1
3
3
.4.1 6-Chloro-5-nitronicotinonitrile (4b). Yield – 2,003 mg (73%). Yellow solid, m.p. 112-
1
13
6 6
15 °С. H NMR (DMSO-d , 300 K, ppm) δ 9.14 - 9.20 (m, 2H, HPy). C NMR (DMSO-d ,
6 2 3 2
00 K, ppm) δ 158.7, 153.4, 149.2, 144.0, 137.6, 120.3. Anal. Calcd for C H ClN O : C,
9.26; H, 1.10; N 22.89. Found: C, 39.17; H, 1.10; N, 23.01.
4
.4.2 5-Bromo-2-chloro-3-nitropyridine (4d).Yield – 2,880 mg (81%). Yellow solid, m.p. 66-
1
13
6
8 °C. H NMR (DMSO-d , 300 K, ppm) δ 8.75 - 8.79 (m, 2H, Py). C NMR (DMSO-d ,
6 6
1
0

ACCEPTED MANUSCRIPT
3
1
0
00 K, ppm) δ 153.8, 144.5, 140.3, 137.3, 119.1. IR (NaCl) ν1578,4 (Py), 1556,9 (Py),
534,9 (NO
2 2 5 2 2 2
), 1345,4 (NO ), 1062,73 (C-Br). Anal. Calcd for C H BrClN O : C, 25.29; H,
.85; N 11.80. Found: C, 25.22; H, 0.85; N, 11.87.
2
1
4
.4.3 2-Chloro-3-nitro-5-trifluoromethylpyridine (4e). Yield – 2,440 mg (72%). Yellow
1
solid, m.p. 101-103 °С. H NMR (DMSO-d
6
, 300 K, ppm) δ 9.23 (s, 1H, Py), 9.10 (s, 1H,
, 300 K, ppm) δ 156.0, 143.9, 141.4, 136.3, 129.1, 122.2. Anal.
: C, 31.81; H, 0.89; N 12.37. Found: C, 31.72; H, 0.89; N, 12.40.
1
3
Py). C NMR (DMSO-d
Calcd for C
6
6
H
2
F
3
N
2
O
2
4
.5 General procedure for preparation of pyrazoles 1e-f.
A 65% aqueous solution of N ·H O (5 mL) was added to a solution of 9 (0.015 mol) in
2
H
4
2
ethanol (50 mL). The resulting mixture was heated at reflux for 2 h, cooled to r. t. and poured
over crushed ice-H O mixture (500 mL total volume). The resulting precipitate was collected
2
by filtration, washed with cold i-PrOH, air dried and further dried at 60 °C overnight.
4
.5.1 2-[3-(Trifluoromethyl)-1H-pyrazol-5-yl]phenol (1e). The spectral data of the compound
13 1
obtained were consistent with the ones published: H NMR (DMSO-d , 300 K, ppm) δ
6
1
1
3.59 (br s, 1H, OH), 10.39 (br s, 1H, NH), 7.67 (d, J =7 .5 Hz, 1H, HAr), 7.22 (t, J = 7.5 Hz,
H, HAr), 7.08 (s, 1H, HPyrazole), 7.00 (d, J = 8.5 Hz, 1H, HAr), 6.90 (t, J = 7.2 Hz, 1H, HAr). IR
(
NaCl) ν 3408 (OH), 3148 (NH), 1279 (Ar-OH), 1250 (Ar-OH), 1150 (CF
3
3
), 1122 (CF ), 747
1
3
(
CF3). C NMR (DMSO-d , 300 K, ppm) δ 154.2, 141.5 (q, J = 95.0 Hz), 129.9, 127.8,
6
1
21.0 (q, J = 267.0 Hz), 119.4 (q, J = 6.0 Hz), 116.3, 102.4.
4
.5.2 Methyl 5-(2-hydroxyphenyl)-1H-pyrazole-3-carboxylate (1f). The spectral data of the
14 1
compound obtained were consistent with the ones published: H NMR (DMSO-d , 300 K,
6
ppm) δ 8.37 (d, J = 7.9 Hz, 1H, HAr), 7.88 (s, 1H, HPyrazole), 7.83 (t, J = 7.9 Hz, 1H, HAr), 7.63
1
3
(
d, J = 8.5 Hz, 1H, HAr), 7.52 (t, J = 7.2 Hz, 1H, HAr), 4.49 (s, 3H, COOMe). C NMR
DMSO-d , 300 K, ppm) δ 179.3, 161.2, 154.7, 152.3, 134.1, 125.3, 122.9, 119.7, 116.8,
(
6
s51.5.
.6 General procedure for preparation of benzo[f]pyrazolo[1,5-d]pyrido[3,2-b][1,4]oxa-
4
zepines 3.
2 3
A mixture of 1 (10 mmol), 4 (10 mmol) and K CO (1.15 g, 30 mmol) in dry DMF (15 mL)
was stirred at an appropriate temperature (in the 40-110 °C range) until the reaction went to
completion (8-36 h), then cooled down to r. t.And concentrated under reduced pressure. The
1
1

ACCEPTED MANUSCRIPT
residue was diluted with water (100 mL); the resulting precipitate was filtered off and
crystallized from the solvent system indicated to provide the title compound.
4
.6.1 10-(Trifluoromethyl)benzo[f]pyrazolo[1,5-d]pyrido[3,2-b][1,4]oxazepine (3a). Grey
1
solid, m.p. 107-109 °C (C
6
H
14/i-PrOH). H NMR (DMSO-d
6
, 300 K, ppm): δ 8.85 (s, 1H,
H
H
Py), 8.59 (s, 1H, HPy), 8.05 (s, 1H, HPyrazole), 7.78 (d, J = 8.5 Hz, 1H, HAr), 7.49-7.63 (m, 2H,
13
6
Ar), 7.41 (t, J = 6.2 Hz, 1H, HAr), 7.08 (s, 1H, HPyrazole). C NMR (DMSO-d , 300 K, ppm):
δ 163.9, 155.2, 146.3, 143.3, 142.0 (q, J = 10.8 Hz), 140.4, 131.9 (q, J = 12.0 Hz), 129.8,
26.7, 126.5, 125.1 (q, J = 95.0 Hz), 121.2, 121.0, 120.0 (q, J = 261.0 Hz), 108.1. Anal.
Calcd for C15 O: C, 59.41; H, 2.66; N 13.86. Found: C, 59.23; H, 2.66; N, 13.93.
1
7 3 3
H F N
4
.6.2 Methyl benzo[f]pyrazolo[1,5-d]pyrido[3,2-b][1,4]oxazepine-10-carboxylate (3b). Off-
1
6 6
white solid, m.p. 175-177 °C (C H14/i-PrOH). H NMR (DMSO-d , 300 K, ppm): δ 8.91 (s,
1
H, HPy), 8.47 (s, 1H, HPy), 8.03 (s, 1H, HPyrazole), 7.76 (d, J = 7.9 Hz, 1H, HAr), 7.64 (d, J =
.9 Hz, 1H, H ), 7.54 (t, J = 7.5 Hz, 1H, H ), 7.38 (t, J = 7.5 Hz, 1H, H ), 7.06 (s, 1H,
7
Ar
Ar
Ar
1
3
H
Pyrazole), 3.92 (s, 3H, COOCH
3
). C NMR (DMSO-d
6
, 300 K, ppm): δ 164.1, 155.2, 146.9,
1
46.4, 145.5, 143.2, 140.5, 132.0, 131.7, 129.5, 126.8, 126.3, 121.4, 121.2, 108.2, 52.7.
Anal.Calcd for C H N O : C, 65.53; H, 3.79; N 14.33. Found: C, 65.33; H, 3.78; N, 14.38.
1
6
11
3
3
4
1
1
7
.6.3 10-Nitrobenzo[f]pyrazolo[1,5-d]pyrido[3,2-b][1,4]oxazepine (3c). Yellow solid, m.p.
1
86-188 °C (C
6
H
14/i-PrOH). H NMR (DMSO-d
6
, 300 K, ppm): δ 9.24 (s, 1H, HPy), 8.92 (s,
H, H ), 8.09 (s, 1H, H
), 7.79 (d, J = 7.5 Hz, 1H, H ), 7.67 (d, J = 7.9 Hz, 1H, H ),
Py
Pyrazole
Ar
Ar
1
3
.57 (d, J = 7.9 Hz, 1H, HAr), 7.41 (t, J = 7.5 Hz, 1H, HAr), 7.11 (s. 1H, HPyrazole). C NMR
, 300 K, ppm): δ 157.0, 156.3, 147.8, 145.1, 144.6, 141.2, 133.1, 132.7, 128.3,
26.7, 122.5, 120.2, 119.5, 115.3. Anal. Calcd for C H N O : C, 60.00; H, 2.90; N 14.99.
(DMSO-d
6
1
14
8
4
3
Found: C, 59.84; H, 2.88; N, 15.07.
4
.6.4 10-Bromo-2-ethylbenzo[f]pyrazolo[1,5-d]pyrido[3,2-b][1,4]oxazepine (3d). Grey solid,
1
6 6
mp 174-176 °C (C H14/i-PrOH). H NMR (DMSO-d , 300 K, ppm): δ 8.53 (s, 1H, HPy), 8.40
(s, 1H, HPy), 7.72 (d, J = 7.5 Hz, 1H, HAr), 7.49-7.60 (m, 2H, HAr), 7.36 (t, J = 7.1 Hz, 1H,
H
Ar), 6.86 (s, 1H, HPyrazole), 2.64-2.80 (m, 2H, CH
2
CH
, 300 K, ppm): δ 156.9, 155.2, 146.3, 145.8, 143.3, 140.5, 133.8, 131.4,
29.4, 126.7, 121.4, 121.2, 117.8, 16.4, 21.2, 13.4. Anal.Calcd for C16 O: C, 58.46;
H, 3.67; N 12.78. Found: C, 58.31; H, 3.68; N, 12.85.
3 2 3
), 1.28 (t, J = 7.9 Hz, 3H, CH CH ).
1
3
C NMR (DMSO-d
6
1
H12BrN
3
1
2

ACCEPTED MANUSCRIPT
4
.6.5 2-Ethyl-10-(trifluoromethyl)benzo[f]pyrazolo[1,5-d]pyrido[3,2-b][1,4]oxazepine (3e).
1
Off-white solid, m.p. 133-135 °C (C H /i-PrOH). H NMR (DMSO-d , 300 K, ppm): δ 8.80
6
14
6
(
s, 1H, HPy), 8.54 (s, 1H, HPy), 7.74 (d, J = 7.5 Hz, 1H, HAr), 7.50-7.60 (m, 2H, HAr), 7.38 (t,
J=7.9 Hz, 1H, HAr), 6.94 (s, 1H, HPyrazole), 2.66-2.81 (m, 2H, CH CH ), 1.29 (t, J = 7.9 Hz,
, 300 K, ppm): δ 158.3, 154.9, 147.0, 145.2, 142.5 (q, J =
3.2 Hz), 141.0, 131.6, 129.4, 129.0 (q, J = 10.3 Hz), 128.4, 126.8, 124.7 (q, J = 99.3 Hz),
2
3
1
3
3
1
1
3
2 3 6
H, CH CH ). C NMR (DMSO-d
12 3 3
21.3, 106.9, 118.2 (q, J = 273.0 Hz) 21.2, 13.2. Anal. Calcd for C17H F N O: C, 61.63; H,
.64; N 12.68. Found: C, 61.45; H, 3.65; N, 12.75.
4
.6.6 2-Ethylbenzo[f]pyrazolo[1,5-d]pyrido[3,2-b][1,4]oxazepine-10-carbonitrile (3f). White
1
solid, m.p. 179-181 °C (C H /i-PrOH). H NMR (DMSO-d , 300 K, ppm): δ 8.92 (s, 1H,
6
14
6
H
Py), 8.57 (s, 1H, HPy), 7.79 (d, J = 7.6 Hz, 1H, HAr), 7.54-7.61 (m, 2H, HAr), 7.41 (t, J = 7.5
Hz, 1H, HAr), 6.98 (s, 1H, HPyrazole), 2.67-2.82 (m, 2H, CH CH ), 1.29 (t, J = 7.9 Hz, 3H,
CH CH ). C NMR (DMSO-d , 300 K, ppm): δ 157.2, 156.1, 146.8, 145.3, 143.4, 141.2,
2
3
1
3
2
3
6
1
33.8, 131.7, 128.9, 126.5, 121.6, 121.2, 117.5, 117.2, 116.8, 21.1, 13.4. Anal. Calcd for
O: C, 62.20; H, 3.68; N 17.07. Found: C, 62.02; H, 3.69; N, 17.07.
17 12 4
C H N
4
.6.7 2,5-Dimethylbenzo[f]pyrazolo[1,5-d]pyrido[3,2-b][1,4]oxazepine (3g). Grey solid,
1
m.p. 115-117 °C (i-PrOH). H NMR (DMSO-d
6
, 300 K, ppm): δ 8.36 (d, J = 3.9 Hz, 1H, HPy),
7
1
.95 (d, J = 7.9 Hz, 1H, HPy),7.43-7.59 (m, 2H, HPy+HAr), 7.29-7.40 (m, 2H, HAr), 6.74 (s,
13
H, HPyrazole), 2.34 (s, 3H, PyrazoleCH ), 2.31 (s, 3H, ArCH ). C NMR (DMSO-d , 300 K,
3
3
6
ppm): δ 158.9, 148.7, 146.0, 144.5, 143.2, 142.1, 141.5, 135.2, 134.1, 132.5, 128.7, 126.4,
1
7
20.5, 119.5, 21.4, 13.5. Anal.Calcd for C16
2.77; H, 4.98; N, 16.09.
13 3
H N O: C, 72.99; H, 4.98; N 15.96. Found: C,
4
.6.8 Methyl 2,5-dimethylbenzo[f]pyrazolo[1,5-d]pyrido[3,2-b][1,4]oxazepine-10-carbo-
1
xylate (3h). White solid, m.p. 190-192 °C (C
6
H
14/i-PrOH). H NMR (DMSO-d
6
, 300 K,
ppm): δ 8.86 (s, 1H, HPy), 8.39 (s, 1H, HPy), 7.51 (s, 1H, HAr), 7,48 (d, J = 8.5 Hz, 1H, HAr),
7
.30 (d, J = 9.5 Hz, 1H, HAr), 6.84 (s, 1H, HPyrazole), 3.91 (s, 3H, COOCH
3
), 2.35 (s, 3H,
13
PyrazoleCH
3
), 2.32 (s, 3H, ArCH
3
). C NMR (DMSO-d
6
, 300 K, ppm): δ 162.1, 153.1,
1
5
4
51.9, 147.0, 146.2, 145.2, 141.2, 136.1, 132.0, 131.4, 129.4, 128.8, 120.9, 120.8, 107.9,
15 3 3
2.7, 20.3, 13.5. Anal. Calcd for C18H N O : C, 67.28; H, 4.71; N 13.08.Found: C, 67.08; H,
.71; N, 13.14.
4
.6.8 2,5-Dimethyl-10-nitrobenzo[f]pyrazolo[1,5-d]pyrido[3,2-b][1,4]oxazepine (3i). Yellow
1
solid, m.p. 175-177 °C (i-PrOH). H NMR (DMSO-d
6
, 300 K, ppm): δ 9.19 (s, 1H, HPy), 8.82
1
3

ACCEPTED MANUSCRIPT
(s, 1H, HPy), 7.53 (d, J = 6.6 Hz, 1H, HAr), 7.49 (s, 1H, HAr), 7.34 (d, J = 8.5 Hz, 1H, HAr),
1
3
6
3
1
.89 (s, 1H, HPyrazole), 2.36 (s, 3H, PyrazoleCH ), 2.33 (s, 3H, ArCH ). C NMR (DMSO-d ,
3 3 6
00 K, ppm): δ 159.7, 148.0, 145.4, 144.1, 143.5, 141.7, 141.5, 135.0, 133.9, 132.7, 128.4,
25.4, 121.4, 117.5, 21.5, 13.5. Anal.Calcd for C16 : C, 62.33; H, 3.92; N 18.17.
12 4 3
H N O
Found: C, 52.15; H, 3.93; N, 18.26.
4
.6.9 5-Chloro-2-methylbenzo[f]pyrazolo[1,5-d]pyrido[3,2-b][1,4]oxazepine (3j). Off-white
1
solid, m.p. 133-135 °C (i-PrOH). H NMR (DMSO-d
6
, 300 K, ppm): δ 8.39 (d, J = 4.3 Hz,
1
H, HPy), 8.00 (d, J = 7.9 Hz, 1H, HPy), 7.77 (s, 1H, HAr), 7.44-7.59 (m, 3H, HAr+HPy), 6.87
13
(
s, 1H, HPyrazole), 2.34 (s, 3H, CH
3
). C NMR (DMSO-d
6
, 300 K, ppm): δ 160.1, 147.4,
1
1
3
46.3, 145.1, 144.0, 142.3, 141.7, 136.3, 133.7, 132.1, 129.2, 127.4, 125.4, 121.5, 120.0,
08.3, 14.2. Anal. Calcd for C17
.56; N, 14.88.
3
H10ClN O: C, 63.50; H, 3.55; N 14.81.Found: C, 63.31; H,
4
.6.10 Methyl 5-chloro-2-methylbenzo[f]pyrazolo[1,5-d]pyrido[3,2-b][1,4]oxazepine-10-
1
carboxylate (3k). Beige solid, m.p. 152-154 °C (i-PrOH). H NMR (DMSO-d
6
, 300 K, ppm):
δ 8.87 (s, 1H, HPy), 8.45 (s, 1H, HPy), 7.80 (s, 1H, HAr), 7.67 (d, J = 8.9 Hz, 1H, HAr), 7.58 (d,
13
J = 8.8 Hz, 1H, H ), 6.94 (s, 1H, H
), 3.94 (s, 3H, COOCH ), 2.31 (s, 3H, CH ). C
3 3
Ar
Pyrazole
NMR (DMSO-d
6
, 300 K, ppm): δ 154.8, 150.4, 148.2, 144.2, 143.1, 140.9, 139.2, 132.0,
1
1
5
31.4, 127.9, 126.5, 124.8, 122.7, 110.8, 107.6, 14.1. IR (NaCl) ν1716 (C=O), 1596 (Py),
581 (Py), 1307 (C-O-C), 1240 (Ar-O-Ar), 770 (C-Cl). Anal. Calcd for C17
9.75; H, 3.54; N 12.30.Found: C, 59.57; H, 3.54; N, 12.36.
3 3
H12ClN O : C,
4
.6.11 5-Chloro-2-methyl-10-nitrobenzo[f]pyrazolo[1,5-d]pyrido[3,2-b][1,4]oxazepine (3l).
1
Grey solid, m.p. 184-186 °C (i-PrOH). H NMR (DMSO-d
6
, 300 K, ppm): δ 9.21 (s, 1H,
H
Py), 8.90 (s, 1H, HPy), 7.83 (s, 1H, HAr), 7.68 (d, J = 8.9 Hz, 1H, HAr), 7.61 (d, J = 9.2 Hz,
1
3
1
1
1
2
H, HAr), 7.04 (s, 1H, HPyrazole), 2.36 (s, 3H, CH
3 6
). C NMR (DMSO-d , 300 K, ppm): δ
53.1, 152.6, 147.4, 143.8, 143.1, 141.3, 139.7, 131.1, 130.7, 128.4, 126.9, 123.2, 122.6,
09.5, 13.4.Anal. Calcd for C15
.76; N, 17.13.
9 4 3
H ClN O : C, 54.81; H, 2.76; N 17.04. Found: C, 54.67; H,
4
.6.12 2-(Trifluoromethyl)benzo[f]pyrazolo[1,5-d]pyrido[3,2-b][1,4]oxazepine (3m). White
1
solid, m.p. 118-120 °C (i-PrOH). H NMR (DMSO-d
6
, 300 K, ppm): δ 8.48 (d, J = 3.8 Hz,
1
H, HPy), 8.11 (d, J = 7.5 Hz, 1H, HPy), 7.82 (d, 1H, J = 7.5, HAr), 7.53-7.68 (m, 3H,
1
3
H +H ), 7.52 (s, 1H, H
), 7.41 (t, 1H, J = 7.0 Hz, H ). C NMR (DMSO-d , 300 K,
Ar 6
Py
Ar
Pyrazole
ppm): δ 156.0, 147.0, 146.0 (q, J = 99.8 Hz), 142.9, 132.4, 131.7, 129.8, 126.8, 126.3, 121.5
1
4

ACCEPTED MANUSCRIPT
8 3 3
(q, J = 254.0 Hz), 121.2, 120.3 (q, J = 6.9 Hz), 105.2. Anal. Calcd for C15H F N O: C, 59.41;
H, 2.66; N 13.86. Found: C, 59.23; H, 2.66; N, 13.93.
4
.6.13
10-Bromo-2-(trifluoromethyl)benzo[f]pyrazolo[1,5-d]pyrido[3,2-b][1,4]oxazepine
1
(3n). Grey solid, m.p. 209-211 °C (C
6
H
14/i-PrOH). H NMR (DMSO-d
6
, 300 K, ppm): δ 8.64
(s, 1H, HPy), 8.65 (s, 1H, HPy), 7.84 (d, J = 7.9 Hz, 1H, HAr), 7.57-7.63 (m, 3H, HAr+HPyrazole),
1
3
7
.44 (t, J = 6.2 Hz, 1H, HAr). C NMR (DMSO-d
99.8 Hz), 142.1, 134.4, 132.5, 129.9, 126.9, 121.5 (q, J = 264.0 Hz), 122.1, 121.3, 120.0 (q,
J = 10.5 Hz), 105.4. IR (NaCl) ν 1578 (Py), 1506 (Py),1248 (C-O-C), 1126 (Ar-O-Ar), 1087
C-Br), 748 (CF ). Anal. Calcd for C15 BrF O: C, 47.15; H, 1.85; N 11.09. Found: C,
7.14; H, 1.86; N, 11.05.
6
, 300 K, ppm): δ 156.5, 146.7, 143.0 (q, J
=
(
3
H
7
3 3
N
4
4
.6.14
2-(Trifluoromethyl)benzo[f]pyrazolo[1,5-d]pyrido[3,2-b][1,4]oxazepine-10-
1
carbonitrile (3o). Beige solid, m.p. 215-218 °C (C
6
H
14/i-PrOH). H NMR (DMSO-d
6
, 300 K,
ppm): δ 8.91 (s, 1H, HPy), 8.52 (s, 1H, HPy), 7.87 (d, J = 7.5 Hz, 1H, HAr), 7.61-7.68 (m, 3H,
13
H +H
Ar
), 7.45 (t, J = 6.0 Hz, 1H, H ). C NMR (DMSO-d , 300 K, ppm): δ 155.9,
Ar 6
Pyrazole
1
1
1
56.5, 144.7 (q, J = 98.0 Hz), 142.7, 142.3, 134.9, 132.2 (q, J = 10.8 Hz), 127.0, 122.9,
7 3 4
21.2, 120.0 (q, J = 8.0 Hz), 118.1, 105.3. Anal. Calcd for C16H F N O: C, 58.54; H, 2.15; N
7.07. Found: C, 58.37; H, 2.15; N, 17.15.
4
.6.15 Methyl 10-bromobenzo[f]pyrazolo[1,5-d]pyrido[3,2-b][1,4]oxazepine-2-carboxylate
1
(3p). Grey solid, m.p. 163-165 °C (C
6
H
14/i-PrOH). H NMR (DMSO-d
6
, 300 K, ppm): δ 8.62
(
s, 1H, H ), 8.52 (s, 1H, H ), 7.84 (d, J = 7.5 Hz, 1H, H ), 7.53-7.61 (m, 2H, H ), 7.47 (s,
Py Py Ar Ar
13
1
3 6
H, HPyrazole), 7.31 (t, J = 6.4 Hz, 1H, HAr), 3.91 (s, 3H, COOCH ). C NMR (DMSO-d , 300
K, ppm): δ 155.9, 154.1, 145.4, 143.9, 142.7, 140.4, 131.3, 131.0, 129.3, 129.2, 126.3, 121.2,
1
5
21.1, 107.4, 52.2. Anal. Calcd for C16
1.48; H, 2.71; N, 11.35.
3 3
H10BrN O : C, 51.64; H, 2.71; N 11.29. Found: C,
4
.6.16 Methyl 10-(trifluoromethyl)benzo[f]pyrazolo[1,5-d]pyrido[3,2-b][1,4]oxazepine-2-
1
carboxylate (3q). Grey solid, m.p. 164-166 °C (C
6
H
14/i-PrOH). H NMR (DMSO-d
6
, 300 K,
ppm): δ 8.88 (s, 1H, HPy), 8.64 (s, 1H, HPy), 7.86 (d, J = 7.9 Hz, 1H, HAr), 7.56-7.64 (m, 2H,
1
3
H
Ar), 7.51 (s, 1H, HPyrazole), 7.41 (t, J = 6.8 Hz, 1H, HAr), 3.92 (s, 3H, COOCH
DMSO-d , 300 K, ppm): δ 161.5, 155.1, 146.2 (q, J = 11.0 Hz), 145.7, 142.4, 132.2, 129.8,
26.9, 126.3 (q, J = 66.0 Hz), 122.2 (q, J = 273.0 Hz), 120.3, 109.3, 52.2. Anal. Calcd for
3
). C NMR
(
6
1
C H F N O : C, 56.52; H, 2.79; N 11.63. Found: C, 56.53; H, 2.79; N, 11.69.
17
10
3
3
3
1
5

ACCEPTED MANUSCRIPT
4
.6.17 Methyl 10-cyanobenzo[f]pyrazolo[1,5-d]pyrido[3,2-b][1,4]oxazepine-2-carboxylate
1
(
3r). Off-white solid, m.p. 179-181 °C (C H /i-PrOH). H NMR (DMSO-d , 300 K, ppm): δ
6
14
6
8
7
.94 (s, 1H, HPy), 8.50 (s, 1H, HPy), 7.89 (d, J = 7.7 Hz, 1H, HAr), 7.60-7.68 (m, 2H, HAr),
13
.46 (s, 1H, HPyrazole), 7.28 (t, J = 6.7 Hz, 1H, HAr), 3.95 (s, 3H, COOCH
3
). C NMR
(DMSO-d
6
, 300 K, ppm): δ 157.2, 155.3, 146.7, 144.4, 143.5, 139.7, 131.4, 131.3, 129.7,
1
3
29.3, 126.7, 124.3, 121.5, 110.3, 108.6, 52.7. Anal. Calcd for C17
.17; N 17.60. Found: C, 63.91; H, 3.18; N, 17.67.
10 4 3
H N O : C, 64.15; H,
Acknowledgements
Mikhail Krasavin acknowledges support from Griffith University.
Supplementary data
The supplementary data containing NMR spectra of the reaction products is available on
http://www.sciencedirect.com.
References and notes
1
2
. Radl, S. Adv. Heterocycl. Chem.2002, 83, 189.
. Sapegin, A. V.; Sakharov, V. N.; Kalandadze, L. S.; Smirnov, A. V.; Khristolyubova, T.
A.; Plakhtinskii, V. V.; Ivashchenko, A. V. Mendeleev Commun.2008, 18, 281.
3
4
5
. Liu, Y.; Chu, C.; Huang, A.; Zhan, C.; Ma, Y.; Ma, C. ACS Comb. Sci.2011, 13, 547
2
(
unfortunately, our prior work was not referenced in this paper).
. Sapegin, A. V.; Kalinin, S. A.; Smirnov, A. V.; Dorogov, M. V.; Krasavin, M.
Synthesis2012, 44, 2401.
. (a) Davies, J. M. Am. J. Psychiatry1976, 133, 208 (psychotropic activity); (b) Hallinan, E.
A.; Stapelfeld, A.; Savage, M. A.; Reichman, M. Bioorg. Med. Chem. Lett.1994, 4, 509
(prostaglandin receptor antagonism); (c) Dols, P. P. M. A.; Folmer, B. J. B.; Hamersma,
H.; Kuil, C. W.; Lucas, H.; Ollero, L.; Rewinkel, J. B. M.; Hermkens, P. H. H. Bioorg.
Med. Chem. Lett.2008, 18, 1461 (progesetrone receptor antagonism); (d) Dorn, A.;
Schattel, V.; Laufer, S. Bioorg. Med. Chem. Lett.2010, 20, 3074 (p38 MAP kinase
inhibition); (e) Gijsen, H. J. M.; Berthelot, D.; Zaja, M.; Brone, B.; Geuens, I.; Mercken,
M. J. Med. Chem.2010, 53, 7011 (ion channel modulation); (f) Binaschi, M.; Boldetti, A.;
Gianni, M.; Maggi, C. A.; Gensini, M.; Bigioni, M.; Parlani, M.; Giolitti, A.; Fratelli, M.;
Valli, C.; Terao, M.; Garattini, E. ACS Med. Chem. Lett.2010, 1, 411 (inhibition of
histone deacetylases).
1
6

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8
9
1
. Evans, B. E. J. Med. Chem. 1988, 31, 2235.
. Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem.2009, 52, 6752.
. Ishikawa, M.; Hashimoto, Y. J. Med. Chem.2011, 54, 1539.
. Karcher, S. C.; Laufer, S. A. J. Med. Chem.2009, 52, 1778.
0. Castaneda, I. C. H.; Vedova, C. O. D.; Jios, J. L.; Ulic, S. E.; Metzer-Nolte, N.
Tetrahedron Lett.2011, 52, 1436.
1
1
1. Seidel, D.; Conrad, M.; Schoof, Y.; Schohe-Loop, R. J. J. Label. Compd.
Radiopharm.2002, 45, 1115.
2. Crystallographic data (excluding structure factors) for the structure 3l have been
deposited with the Cambridge Crystallographic Data Centre as supplementary publication
number CCDC 944143. Copies of the data can be obtained free of charge, on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44(0)-1223-336033 or e-
mail: deposit@ccdc.cam.ac.uk].
1
1
3. Sosnovskikh,V. Ya.; Barabanov, M. A.; Sizov, A. Yu. Russ. Chem. Bull.2002, 51, 1280.
4. Varano, F.; Catarzi, D.; Colotta, V.; Cecchi, L.; Filacchioni, G.; Galli, A.; Costagli, C.
Arch. Pharm. Pharm. Med. Chem.1996, 329, 529.
1
1
1
1
1
2
2
5. Sawada, K.; Inoue, T.; Sawada, Y.; Mizutani, T. PCT Int. Appl. (2001)
WO2001005770A1, 159 pp.; Chem, Abstr. 2001, 134, 100871.
6. Flatt, A. K.; Dirk, S. M.; Henderson, J. C.; Shen, D. E.; Su, J.; Reed, M. A.; Tour, J. M.
Tetrahedron 2003, 59, 8555-8570.
7. Cai, S. X.; Huang, J.-C.; Espitia, S. A.; Tran, M.; Ilyin, V. I.; Hawkinson, J. E.;
Woodward, R. M.; Weber, E.; Keana, J. F. W. J. Med. Chem. 1997, 40, 3679-3686.
8. Kato, T.; Kon-I, K.; Yuki, Y.; Ando, K. PCT Int. Appl. (2007) WO2007102059A1;
Chem. Abstr. 2007, 147, 365499.
9. Xue, C.-B.; Zheng, C.; Feng, H.; Xia, M.; Glenn, J.; Cao, G.; Metcalf, B. W. PCT Int.
Appl. (2006) WO2006004741A2; Chem. Abstr. 2006, 144,108363.
0. Goodman, K. B.; Sehon, C. A.; Cleary, P. A.; Philip, J.; Peace, S. PCT Int. Appl. (2007)
WO2007067875A2; Chem. Abstr. 2007, 147, 72643.
1. Robinson, R. P.; Donahue, K. M.; Son, P. S.; Wagy, S. D. J. Heterocycl. Chem. 1996, 33,
2
87-293.
1
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ACCEPTED MANUSCRIPT
Supporting Information
for
New tetracyclic 1,4-oxazepines constructed via practically simple tandem
condensation strategy from readily available synthons
Alexander V. Sapegin, Stanislav A. Kalinin, Alexey V. Smirnov, Mikhail V. Dorogov and Mikhail Krasavin
1
13

Copies of H and C NMR spectra for compounds 1e-f, 4b, 4d-e, 5a-c, 8a-b, 9a-b, 3a-r

ACCEPTED MANUSCRIPT
©
Zelinsky Institute of Organic Chemistry, Moscow; Bruker DRX500 SF=125.76 MHz {13C} SI=64K SW=31443 O1=13309 PW=8.0 AQ=0.521 RD=0.50 NS=1140 SR=115.76 TE=299K 18 June 2013 Opr: Strelenko Yu.A.; Prep: L−8402; Solv: DMSO−d6;
NMR/23217525
Compound 1e
190
180
170
160
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
ppm

ACCEPTED MANUSCRIPT
F
SAV09_1
F
F
N
N
H
OH
Compound 1e
1
3.0
12.0
11.0
Operator:
Solvent:
10.0
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
File name: SAV09_1
Date: 30-Nov-1999
SF: 300.1300 MHz
SW: 5376 Hz
NSC: 8
PW: 0.00 usec, RG: 0
SI: 16384
TE: 297 K
AQ: 2.24 sec, RD: 0.00 sec

ACCEPTED MANUSCRIPT
ꢉIꢀA,ꢂꢂAꢀ
Compound 1f
QꢀA
QꢁA
QꢂA
QꢃA
QꢄA
QꢅA
QIA
QQA
QAA
ꢆA
ꢀA
ꢁA
ꢂA
ꢃA
ꢄA
ꢅA
IA
QA
ꢊꢋꢌꢍSꢎꢏꢐꢍꢑSꢉIꢀA,ꢂꢂAꢀ
ꢖꢗꢍꢘꢏꢓꢙꢘꢑS
ꢚꢊꢑSQAARꢂꢀAꢁSꢈꢝꢞ
ꢚꢟꢑSIꢄAꢅꢀSꢝꢞ
ꢠꢚꢜꢑSQAIꢄA
ꢇꢟꢑSARAASꢕꢤꢍꢥcSꢦꢧꢑSꢅIꢁꢂꢀ
ꢨꢩꢑSQRꢅꢂSꢤꢍꢥcSꢦꢒꢑSARAASꢤꢍꢥ
ꢚꢪꢑSꢅIꢁꢂꢀ
ꢒꢏꢓꢍꢑSIA,ꢔꢕꢎ,IAQꢅ
ꢚꢙꢌꢛꢍꢎꢓꢑSꢜꢒꢜꢌꢅ
ꢡꢢꢑSꢅAASꢣ
ꢜꢒꢜꢌꢅ

ACCEPTED MANUSCRIPT
ꢂ
ꢊꢋꢌꢇꢁ
ꢂ
ꢃꢁꢄ
ꢀ
ꢀ
ꢁ
ꢃꢁꢄ
Compound 1f
IQRQ
ꢀRQ
ꢁRQ
ꢂRQ
ꢃRQ
ꢄRQ
ꢅRQ
ꢆRQ
ꢇRQ
IRQ
ꢍꢎꢏꢐOꢑꢒꢓꢐꢔOꢊꢋꢌꢇꢁ
ꢕꢒꢖꢐꢔOꢆQ,ꢗꢘꢙ,Iꢀꢀꢀ
ꢚꢛꢐꢜꢒꢖꢘꢜꢔO
ꢊꢍꢔOꢆQQRIꢆQQOꢉꢝꢞ
ꢊꢟꢔOꢄꢆꢂꢃOꢝꢞ
ꢗꢊꢠꢔOIꢃ
ꢈꢟꢔOQRQQOꢤꢥꢐꢦcOꢧꢨꢔOꢅ
ꢊꢪꢔOIꢃꢆꢁꢅ
ꢊꢘꢏꢙꢐꢑꢖꢔO
ꢡꢢꢔOꢇꢀꢂOꢣ
ꢋꢩꢔOꢇRꢇꢅOꢥꢐꢦcOꢧꢕꢔOQRQQOꢥꢐꢦ

ACCEPTED MANUSCRIPT
L280-6591
Compound 3a
180
170
160
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110
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90
80
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30
20
File name: L280-6951
Date: 20-Jun-2013
Operator: SHUM
Solvent: DMSO
SF: 75.4743 MHz
SW: 18797 Hz
NSC: 32768
PW: 0.00 usec, RG: 16384
AQ: 1.74 sec, RD: 0.00 sec
SI: 32768
TE: 353 K
Parameter file, TOPSPINVersion 1.3

ACCEPTED MANUSCRIPT
N
N
SAV18
N
F
O
F
F
Compound 3a
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
File name: SAV18
Date: 30-Nov-1999
Operator:
Solvent:
SF: 300.1300 MHz
SW: 5376 Hz
NSC: 64
TE: 297 K
PW: 0.00 usec, RG: 4
SI: 16384
AQ: 2.24 sec, RD: 0.00 sec

ACCEPTED MANUSCRIPT
L280-6658
N
N
N
O
O
H3C O
Compound 3b
220
200
180
160
140
120
100
80
60
40
20
0
File name: L280-6658
Operator: SHUM
SF: 75.4743 MHz
SW: 18797 Hz
NSC: 32768
PW: 0.00 usec, RG: 16384
AQ: 1.74 sec, RD: 0.00 sec
SI: 32768
Date: 13-Apr-2013
Solvent: DMSO
TE: 353 K
Parameter file, TOPSPINVersion 1.3

ACCEPTED MANUSCRIPT
SAV02
N
N
N
O
O
H3C O
Compound 3b
1
0.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
NSC: 64
TE: 297 K
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
File name: SAV02
Operator:
Solvent:
SF: 300.1300 MHz
SW: 5376 Hz
PW: 0.00 usec, RG: 4
AQ: 2.24 sec, RD: 0.00 sec
SI: 16384
Date: 30-Nov-1999

ACCEPTED MANUSCRIPT
L280-6649
N
N
N
O
+
N O
O
Compound 3c
160
150
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120
110
100
90
80
70
60
50
40
File name: L280-6649
Operator:
SF: 100.6807 MHz
SW: 24038 Hz
NSC: 14613
TE: 300 K
PW: 0.00 usec, RG: 32768
AQ: 1.36 sec, RD: 0.00 sec
SI: 32768
CDCl3
Date: 21-Mar-2013
Solvent: CDCl3

ACCEPTED MANUSCRIPT
SAV13
N
N
N
O
+
N O
O
Compound 3c
1
1.0
10.0
9.0
Operator:
Solvent:
8.0
7.0
SF: 300.1300 MHz
SW: 5376 Hz
6.0
5.0
4.0
3.0
2.0
1.0
File name: SAV13
NSC: 32
PW: 0.00 usec, RG: 0
SI: 16384
Date: 30-Nov-1999
TE: 297 K
AQ: 2.24 sec, RD: 0.00 sec

ACCEPTED MANUSCRIPT
CH3
L280-6652
N
N
N
O
Br
Compound 3d
1
50
140
130
120
110
100
90
NSC: 18720
TE: 295 K
80
70
60
50
40
30
20
File name: L280-6652
Operator: SHUM
Solvent: DMSO
SF: 75.4743 MHz
SW: 18797 Hz
PW: 0.00 usec, RG: 16384
AQ: 1.74 sec, RD: 0.00 sec
SI: 32768
Parameter file, TOPSPINVersion 1.3
Date: 18-Mar-2013